Premium
Retrochalcone derivatives are positive allosteric modulators at synaptic and extrasynaptic GABA A receptors in vitro
Author(s) -
Jiang Ruotian,
Miyamoto Akiko,
Martz Adeline,
Specht Alexandre,
Ishibashi Hitoshi,
KuenyStotz Marie,
Chassaing Stefan,
Brouillard Raymond,
de Carvalho Lia Prado,
Goeldner Maurice,
Nabekura Junichi,
Nielsen Mogens,
Grutter Thomas
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01142.x
Subject(s) - long term potentiation , gabaa receptor , chemistry , allosteric regulation , allosteric modulator , postsynaptic potential , inhibitory postsynaptic potential , neuroactive steroid , receptor , hippocampal formation , biophysics , stereochemistry , biochemistry , neuroscience , biology
BACKGROUND AND PURPOSE Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABA A receptors (GABA A Rs). We previously reported that trans ‐6,4′‐dimethoxyretrochalcone (Rc‐OMe), a hydrolytic derivative of the corresponding flavylium salt, displayed nanomolar affinity for the benzodiazepine binding site of GABA A Rs. Here, we evaluate the functional modulations of Rc‐OMe, along with two other synthetic derivatives trans ‐6‐bromo‐4′‐methoxyretrochalcone (Rc‐Br) and 4,3′‐dimethoxychalcone (Ch‐OMe) on GABA A Rs. EXPERIMENTAL APPROACH Whole‐cell patch‐clamp recordings were made to determine the effects of these derivatives on GABA A Rs expressed in HEK‐293 cells and in hippocampal CA1 pyramidal and thalamic neurones from rat brain. KEY RESULTS Rc‐OMe strongly potentiated GABA‐evoked currents at recombinant α 1–4 β 2 γ 2s and α 4 β 3 δ receptors but much less at α 1 β 2 and α 4 β 3 . Rc‐Br and Ch‐OMe potentiated GABA‐evoked currents at α 1 β 2 γ 2s . The potentiation by Rc‐OMe was only reduced at α 1 H101Rβ 2 γ 2s and α 1 β 2 N265Sγ 2s , mutations known to abolish the potentiation by diazepam and loreclezole respectively. The modulation of Rc‐OMe and pentobarbital as well as by Rc‐OMe and the neurosteroid 3α,21‐dihydroxy‐5α‐pregnan‐20‐one was supra‐additive. Rc‐OMe modulation exhibited no apparent voltage‐dependence, but was markedly dependent on GABA concentration. In neurones, Rc‐Br slowed the decay of spontaneous inhibitory postsynaptic currents and both Rc‐OMe and Rc‐Br positively modulated synaptic and extrasynaptic diazepam‐insensitive GABA A Rs. CONCLUSIONS AND IMPLICATIONS The trans ‐retrochalcones are powerful positive allosteric modulators of synaptic and extrasynaptic GABA A Rs. These novel modulators act through an original mode, thus making them putative drug candidates in the treatment of GABA A ‐related disorders in vivo .